Aims: To analyze
the impact of bleomycin and dacarbazine within the ABVD
regimen.

Methods: The GHSG
HD13 study compared two cycles of ABVD with a dacarbazine-deleted
variant (ABV), a bleomycin-deleted variant (AVD), and a variant in
which both, dacarbazine and bleomycin were deleted (AV). In each
treatment arm, chemotherapy was followed by IFRT of 30 Gy. Primary
objective was to demonstrate non-inferiority of the three
experimental variants compared to ABVD regarding the primary
endpoint freedom from treatment failure (FFTF) by excluding a
difference of 6% after 5 years, corresponding to a non-inferiority
margin of 1.72 for the Hazard Ratio, via a 95% confidence interval
(CI). Recruitment started in 01/2003. In our continuously performed
safety analyses, higher event rates were observed with AV and ABV.
Thus, these two arms were closed early in 09/2005 and 02/2006,
respectively. Randomization between ABVD and AVD continued until
09/2009 with a total of 1710 patients. Two hundred eight patients
were excluded from the final analysis due to revision of HL
diagnosis, loss to follow-up before start of treatment, revision of
staging, or violation of other inclusion criteria. Of 1502
qualified patients analyzed for therapy adherence, toxicity, and
efficacy, 566 were randomized into the standard arm and 198, 571,
and 167 patients were randomized to receive experimental
chemotherapy with ABV, AVD, or AV, respectively.

Results: Patient
characteristics were well balanced between the four treatment arms:
median age was 39 years, 67% had stage II disease, and there were
more male patients included (60%). The most frequent histologic
subtypes were mixed cellularity and nodular sclerosis (40% and 37%,
respectively). The rate of acute toxicities ranged between
26.3% with AVD and 32.7% with ABVD; leukopenia (14.4%), hair loss
(10.9%), and nausea/vomiting (5.8%) were most frequently observed.
Interestingly, pulmonary toxicity was observed in four patients
only, including one patient receiving AV. Only moderate reduction
in acute toxicities was observed when omitting Bleomycin
(leukopenia) and Dacarbazine (nausea/vomiting). FFTF at five years
was 93.1%, 81.4%, 89.2%, and 77.1% after treatment with ABVD, ABV,
AVD, and AV, respectively. Inferiority of the early closed
treatment arms without dacarbazine was confirmed in this final
analysis with five-year-differences in FFTF of 11.5% (95% - CI 4.7%
to 18.3%) with ABV and 15.2% (95% - CI 7.4% to 23.0%) with AV
compared to ABVD, respectively. In addition, non-inferiority of AVD
compared to ABVD could not be confirmed, with a
five-year-difference in FFTF of 3.9% (95% - CI 0.1% to 7.7%). The
respective Hazard Ratio was 1.5 with a 95% - CI ranging from 1.0 to
2.3, including the pre-specified non-inferiority margin. Overall
survival was excellent and did not differ between treatment arms,
with five-year-estimates of 97.6%, 94.1%, 97.6%, and 98.1% after
treatment with ABVD, ABV, AVD, and AV, respectively.

Summary/Conclusion: Dacarbazine cannot be deleted
from the ABVD regimen without a significant loss of efficacy. With
respect to the predefined non-inferiority margin of 6% after 5
years, also Bleomycin cannot be safely omitted. Importantly, the
reduction in tumor control in the experimental arms did not
translate into inferior overall survival.